tbuckley/cabot-search huggingface dataset:
Abstract 2384: Investigating Fis1 upregulation as a stress response in glioblastoma cells
Authors: Yuli Buckley, Adina Brett-Morris, Maria Stoll, Jason Mears
Journal: Cancer Research (2022)

Abstract Dysfunctional mitochondrial dynamics contribute to many pathologies, and elevated levels of mitochondrial fission have been observed in glioblastoma (GBM). Mitochondrial fission 1 protein (Fis1) plays a minor role in basal fission, but has been shown to be more critical for pathological fission. Further, it has been shown to facilitate peripheral fission events, generally occurring after cellular exposure to stress, as a means to prepare damaged mitochondria for degradation through mitophagy. Therefore, my goal is to elucidate the role of Fis1, an integral outer membrane partner protein, in mitochondrial fission within GBM cells. I propose that Fis1 plays a protective role against therapeutic treatment in GBM. This is demonstrated through experiments showing that ionizing radiation (IR) leads to upregulation of Fis1 protein levels, while GBM cell viability is simultaneously unaffected. Further, this increase in Fis1 results in an increase in mitochondrial fission, which likely reflects an increase in mitophagy as a response to IR stress. Thus, I anticipate that GBM cells upregulate Fis1 as a protective measure and that targeting Fis1 function could have therapeutic benefit. In this regard, I have found that depletion of Fis1 alters mitochondrial morphology, and I am studying changes in mitochondrial bioenergetics to correlate ultrastructural changes with mitochondrial function. Preliminary data suggests that Fis1 knockdown in Gli36 cells leads to decreased oxidative phosphorylation and ATP production, with deficits observed specifically in Complex I and III. Concurrently, I am assessing potential synergistic effects of combined radiation and Fis1 inhibition on GBM cell viability and proliferation. To do this, I will use genetic and small molecule approaches to inhibit Fis1-dependent mitochondrial fission. Overall, these studies will demonstrate whether Fis1 drives pathological fission to promote cancer cell growth and proliferation. Additionally, the selective inhibition will evaluate Fis1 as a novel therapeutic target in GBM. Citation Format: Yuli Buckley, Adina Brett-Morris, Maria Stoll, Jason Mears. Investigating Fis1 upregulation as a stress response in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2384.
Modeling spatio-temporal patterns of holistic functional brain networks via multi-head guided attention graph neural networks (Multi-Head GAGNNs)
Authors: Jiadong Yan, Yuzhong Chen, Zhenxiang Xiao, Shu Zhang, Mingxin Jiang, Tianqi Wang, Tuo Zhang, Jinglei Lv, Benjamin Becker, Rong Zhang, Dajiang Zhu, Junwei Han, Dezhong Yao, Keith M. Kendrick, Tianming Liu, Xi Jiang
Journal: Medical Image Analysis (2022)
Abstract 4060: Identification of anti-neoplastic compounds on a triple negative breast cancer cell line from <i>T. violacea</i>
Authors: Zodwa Dlamini, Clement Penny, Rodney Hull, Mohammed Alouna
Journal: Cancer Research (2022)

Abstract Background: The incidence of Invasive triple negative breast cancer (TNBC) is higher than average in South Africa, with 90% of patients being Black South Africans. Current treatments for breast cancer are associated with severe side effects. Additionally, TNBC is resistant to hormone therapy commonly used to treat other forms of breast cancer. Tulbaghia violacea, a plant native to Southern Africa, is a medicinal herb used in traditional medicine. This study aims to establish the impact of water soluble extracts from T. violacea on TNBC cancer cell lines and identify any anti-cancer compounds present in this extract. Methods: Following the determination of the IC50 value for this extract. The anti-proliferative and anti-metastatic activities of the extract on the TNBC cell line were determined using scratch assays and cell invasion and migration assays, performed using real time cell analysis. The pro-apoptotic action of the extract on the TNBC cell line was determined using flow cytometry cell death assays. Once the anti-cancer activity of the extract was confirmed, the composition of the extract was determined in order to establish what known or possible anti-cancer compounds are present within it. This was performed using gas chromatography-mass spectroscopy (GC-MS). The structure of these identified compounds was then confirmed using Nuclear Magnetic Resonance (NMR). Results: The IC50 value for the T. violacea water soluble extract against MDA MB 231 cells was determined to be ~350 µg/mL. The extract was also shown to have anti migration and invasion as well as pro-apoptotic effects on these cells. Fourteen known anti-cancer compounds were identified in this water soluble extract. In addition to this multiple other compounds were shown to also be present in the extract. Discussion: The water soluble T. violacea leaf extract has cytotoxic effects and the ability to inhibit proliferation and metastasis in a TNBC cell line. The identification of fourteen compounds with known anti-cancer activity may explain the effects this extract has on these TNBC cells, however, the contribution made by any of the other compounds to this activity remains to be determined. Conclusion: These findings suggest that one or more of the compounds present in T. violacea may serve as lead compounds for the development of new treatments for TNBC. Citation Format: Zodwa Dlamini, Clement Penny, Rodney Hull, Mohammed Alouna. Identification of anti-neoplastic compounds on a triple negative breast cancer cell line from T. violacea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4060.
Abstract 4015: Primary sites affecting the prognosis of Ewing's sarcoma
Authors: Jun-Qing Mao, Dan Zhao
Journal: Cancer Research (2022)

Abstract Introduction Ewing’s sarcoma (ES) is a small round blue cell malignancy arising from the bone or soft tissue, and most commonly impacts adolescents and young adults. It is difficult to identify those who will likely relapse, however, ES has a very high recurrence rate. Given these realities, the objective of this study was to determine factors influencing the prognosis of ES patients. Methods Clinical and genomic data of 99 patients with ES, were obtained from the cBioPortal. Tumor mutational burden (TMB) and patient survival information were also obtained from the cBioPortal. Results In the data examined, ES had multiple primary sites of disease, including 16 femur, 10 hipbone, 10 rib, 10 tibia, 6 ischium pubis, 5 scapula, 4 fibula, 3 dorsal vertebra, 3 intra-abdominal, 3 lumbar vertebra, and 3 skull. A comparison of survival relationships between different primary sites of ES indicated that overall survival (OS) was significantly different between femur and dorsal vertebra (p = 0.023) and intra-abdominal and hipbone (p = 0.049). However, no significant difference was determined for TMB between the different primary sites. The median value of TMB was 0.23. Data were divided into two groups: high TMB (TMB-H,≥ 0.23 muts/Mb) and low TMB (TMB-L, &amp;lt; 0.23muts/Mb). Interestingly, the OS of patients with TMB-L was significantly higher than that of patients with TMB-H (p = 0.049; 59.45 versus 42.00 months). The presence of metastases at the time of diagnosis was associated with poor OS ( p = 0.023;) and was a clinical factor associated with outcomes having statistical significance. Conclusions Given the heterogeneity in outcomes for patients with ES, additional prognostic factors are needed to optimize clinical decision making. Prognosis was different depending on primary site of ES. Patients with ES in hipbone displayed a better prognosis compared to that in abdomen. Similarly, patients with ES in dorsal vertebra had a significantly higher OS than that in femur. As such, the primary site should perhaps be considered during ES treatment, although there was no significant difference between TMB and primary site. Our results indicate that high TMB is associated with inferior survival for ES and may provide insights for clinical practice. Citation Format: Jun-Qing Mao, Dan Zhao. Primary sites affecting the prognosis of Ewing's sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4015.
Abstract 3717: KMT2D loss cooperates with PTCH loss for medulloblastoma genesis
Authors: Shilpa S. Dhar, Calena J. Brown, Ali S. Rizvi, Janak R. Abraham, Roy V. Sillitoe, Kaifu Chen, Min Gyu Lee
Journal: Cancer Research (2022)

Abstract We have previously reported that the histone H3 lysine 4 methyltransferase KMT2D (also called MLL4, MLL2, and ALR; a transcriptional coactivator) is required for neuronal differentiation of human neuron-committed NT2/D1 embryonal carcinoma stem cells. Notably, we have shown that brain-specific knockout of Kmt2d alone induces spontaneous medulloblastoma (MB) in mice and that Kmt2d loss in the brain highly upregulates several oncogenic signaling programs and downregulates tumor suppressor genes. Consistent with this, our analysis of several publicly available databases indicates that Kmt2d is the most frequently mutated epigenetic modifier (8%‒10%) in MB. In this study, we sought to assess whether Kmt2d loss cooperates with another oncogenic event in MB genesis. Particularly, PTCH (also known as PTCH1), a potent MB-signaling suppressor, is one of the most frequently mutated genes in MB, and KMT2D mutations co-occur with PTCH mutations more than with many other mutations in MB. Therefore, we determined the effect of Kmt2d loss on of Ptch+/--driven MB genesis by generating and analyzing Nestin-Cre Kmt2dfl/+ Ptch+/- mice. Our results showed that heterozygous loss of Kmt2d strongly increased the genesis and incidence of Ptch+/--driven MB. Supporting this, immunohistochemistry staining of Ki-67 (a proliferation marker) showed that heterozygous loss of Kmt2d in Ptch+/--driven MB highly increased the proliferation of MB cells. Our transcriptomic analysis showed that heterozygous Kmt2d loss upregulated tumor-promoting programs, including G-protein-coupled receptor signaling and oxidation-reduction process. In line with this, heterozygous Kmt2d loss upregulated oncogenic kinases (e.g., phospho-AKT1 and phospho-ERK) that may be downstream of G-protein-coupled receptor signaling. Mechanistically, our results indicate that these tumor-promoting programs are repressed, at least in part, by the transcription-repressive and tumor-suppressive factor (s) NCOR2, whose expression is activated by KMT2D. Our results would be the first to provide molecular insights into how co-losses of an epigenetic modifier and an MB-signaling suppressor cooperate for MB genesis. Our new mouse model would be helpful in future preclinical therapeutic experiments for MB treatment. Our findings suggest that targeting oncogenic effectors downstream of KMT2D loss can be considered a potential therapeutic strategy for MB treatment. Citation Format: Shilpa S. Dhar, Calena J. Brown, Ali S. Rizvi, Janak R. Abraham, Roy V. Sillitoe, Kaifu Chen, Min Gyu Lee. KMT2D loss cooperates with PTCH loss for medulloblastoma genesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3717.
Abstract 2035: Imaging mass cytometry identifies structural and cellular composition of the mouse tissue microenvironment
Authors: Qanber Raza, Michael Cohen, Smriti Kala, Liang Lim, Geneve Awong, Andrew Quong, Christina Loh
Journal: Cancer Research (2022)

Abstract Imaging Mass Cytometry™ (IMC™) is a vital tool to deeply characterize the complexity and diversity of any tissue without disrupting spatial context. The Hyperion™ Imaging System utilizes IMC, based on CyTOF® technology, to simultaneously assess up to 40 individual structural and functional markers in tissues, providing unprecedented insight into the organization and function of tissue microenvironment. We have previously demonstrated the application of IMC in combination with Maxpar® panel kits to highlight cellular composition of human tissues. Here, we showcase the recently released Maxpar OnDemand Antibodies for IMC application on mouse tissue. We introduced 11 additional biomarkers to our existing mouse antibody catalog, providing the basis for the use of high-multiplex imaging in preclinical investigations. To demonstrate the IMC workflow on mouse tissue, we analyzed a normal mouse tissue microarray using IMC spatial proteomic analysis. Tissues were stained with a 20-marker panel designed to highlight tissue architecture and major immune lineage markers combined with our IMC Cell Segmentation Kit*. The IMC Cell Segmentation Kit facilitates identification of cellular borders using plasma membrane markers that lead to improved nucleus and plasma membrane demarcation. We generated a detailed spatial map of the heterogeneous tissue architecture and successfully identified immune, epithelial, and stromal cell populations in various mouse tissues. Additionally, we classified the activation state of immune cell populations, adhesion state of epithelial cells, and molecular composition of the extracellular matrix.Overall, this work demonstrates the capability of IMC to identify subcellular localization of cellular and structural markers in the mouse tissue microenvironment. Information gained from IMC studies will enable in-depth high-throughput phenotypic characterization of the tissue microenvironment in various mouse models of development and disease, and thus accelerate preclinical discoveries. *The IMC Cell Segmentation Kit is part of the Innovative Solutions menu of custom-made reagents and workflows developed and tested by Fluidigm scientists to give faster access to new cutting-edge solutions for high-multiplex single-cell analysis. Innovative Solutions are not part of the Maxpar catalog. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Qanber Raza, Michael Cohen, Smriti Kala, Liang Lim, Geneve Awong, Andrew Quong, Christina Loh. Imaging mass cytometry identifies structural and cellular composition of the mouse tissue microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2035.
Abstract LB150: Clinical outcome prediction of prostate cancer using machine learning based on fusion gene detection
Authors: Jian-Hua Luo, Silvia Liu, Yan-Ping Yu
Journal: Cancer Research (2022)

Abstract Prediction of the clinical outcomes of prostate cancer remains a challenge. Recently, we discovered a panel of 8 fusion genes that occurred in aggressive prostate cancer. In order to make the fusion gene test clinically ready as a predictor, we have modified to test into a semi-quantitative Taqman QRT-PCR. In the funding period, Two hundred seventy-one prostate cancer samples with clinical follow-up were collected from University of Pittsburgh Medical Center. In addition, 194 prostate cancer samples from University of Wisconsin, Madison and 108 prostate cancer samples from Stanford University were collected. Taqman QRT-PCRs were performed on these samples. Significant numbers of samples were found positive for some of these fusion genes. The expression of MAN2A1-FER, SLC45A2-AMACR, MTOR-TP53BP1 fusions are associated with prostate cancer recurrence in the UPMC cohort. Cross-validation showed that fusion gene model predicts up to 91% clinical outcomes of prostate cancer accurately. When cohorts of UPMC, Stanford and Wisconsin were combined, the accuracy is 74%. The combination of fusion with Gleason appeared to improve the overall accuracy from 77% (Gleason) to 92% (Gleason+fusion) in the UPMC cohort, and from 71% (Gleason) to 82% (Gleason+fusion) when all three cohorts are combined. When fusion combined with both pathology stage and Gleason, the accuracy was improved a little further: 93% accuracy in the UPMC cohort and 83% when all three cohorts are combined. In summary, fusion transcript prediction model may have a role in prostate cancer prognosis prediction and guiding the management of prostate cancer patients. Citation Format: Jian-Hua Luo, Silvia Liu, Yan-Ping Yu. Clinical outcome prediction of prostate cancer using machine learning based on fusion gene detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB150.
Abstract 2263: The role of E-Cadherin mediated cell division in promoting collective colon cancer cell migration
Authors: Yu-Lin Li, Yu-Cheng Weng, Viriya Adhiguna Winarso, Yi-Wen Lu, Hui Min Koo, Xiang-Ling Hou, Kai-Yu Tseng, Wei-Ting Chao
Journal: Cancer Research (2022)

Abstract Collective cell migration is the cell cohort migrates toward the direction. Other than single cell migration, collective cell migration requires cell-cell connection with E-cadherin, however, E-cadherin is the epithelial marker in epithelial mesenchymal transition and acts as tumor suppressor function. Therefore, the role of E-cadherin in collective cell migration is still under investigated. In the collected cells, cell migration and cell division are coordinated for the cohort motility, the mechanism is still not clear. This study is to investigate the role of E-cadherin orientation in cell division dependent collective cell migration. Colorectal cancer cell line HT29 with epithelial morphology were used and treated with Cetuximab and Dasatinib to inhibit EGFR and Src activity. Cells were also incubated on fibronectin to monitor the matrix dependent environment. The polarity of E-cadherin distribution and cell contact inhibition were defined and detected by Immunofluorescence. The molecular expression of p-FAK, CDK4, and cell proliferation marker, Ki67 were revealed by Immunofluorescence confocal microscopy and Western blot. The collective cell migration is analyzed and compared by wound healing and transwell assay. In the results, the polarized distribution of E-cadherin in leading cells which revealed pFAK expression on the cell membrane was associated with Ki67 and CDK4 positive proliferated cells. When cells were grown on fibronectin, the proliferated cells in the leading were decreased. When cells were treated with cetuximab, the E-cadherin distribution were not changed and had fewer effect on cell migration. However, dasatinib treatment can modulate E-cadherin orientation and suppress cell proliferation and cell migration. These results suggested modulate E-cadherin orientation such as Src inhibition can be the potential treatment strategy in colon cancer Citation Format: Yu-Lin Li, Yu-Cheng Weng, Viriya Adhiguna Winarso, Yi-Wen Lu, Hui Min Koo, Xiang-Ling Hou, Kai-Yu Tseng, Wei-Ting Chao. The role of E-Cadherin mediated cell division in promoting collective colon cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2263.
Abstract 3358: Targeting p63 isoforms in cancer to restore their anti-tumorigenic activity
Authors: E. Sila Ozdemir, Michelle Gomes, Jared Fischer
Journal: Cancer Research (2022)

Abstract p63 plays a central role in limb formation and epithelial differentiation. p63, reported to correlate with cancer formation, is rarely mutated in cancers. Different p63 isoforms can have anti-tumorigenic or pro-tumorigenic activity. TA isoforms act as tumor suppressor by promoting cell death, while deltaN isoforms are strong driver for squamous/squamous-like cancers including lung, head and neck, cervical, skin and pancreas. A large number of tumors are addicted to deltaN isoforms. Furthermore, cancer associated p53R175H mutant gains ability to interact with TAp63 isoforms and inhibit their anti-tumorigenic function, while indirectly promoting tumorigenic function of deltaN isoforms. However, the exact mechanism of p53R175H-p63 interaction is unclear. The changes in the balance of p63 isoform activity are likely to be crucial to understanding the transition between normal cell and tumor formation. Here, we modelled p53R175H-p63 complex using homology modelling, flexible/unbiased docking and molecular dynamics simulations. Moreover, we used our models to design peptides to disrupt p53R175H-p63 interaction and restore anti-tumorigenic function of TAp63 isoforms. Also, we studied deltaN isoform oligomerization and designed peptides to inhibit their oligomerization to reduce their tumorigenic activity. We showed that some of our peptides promoted cell death in a p63 enriched cancel cell line. We characterized our peptides performing kinetic binding assays to validate binding of our peptides to their designated targets. In this study, our computational and experimental analyses presented a detailed model for the p53R175H-p63 interaction. We also provided a framework for potential therapeutic peptides to outweigh the balance in the advantage of anti-tumorigenic p63 activity. Citation Format: E. Sila Ozdemir, Michelle Gomes, Jared Fischer. Targeting p63 isoforms in cancer to restore their anti-tumorigenic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3358.
Abstract 866: Translational repression by a novel partner of human cytoplasmic poly(A) binding protein
Authors: Naren Li, Liang Hu, Qinfang Liu, Yulan Xiong, Jianzhong Yu
Journal: Cancer Research (2022)

Abstract In higher eukaryotes, post-transcriptional regulation of gene expression, which is accomplished by an ensemble of RNA-binding proteins (RBPs), is critical for cellular homeostasis. Unkempt (UNK) is an evolutionarily conserved Zinc Finger/RING domain RNA-binding protein that was originally identified as a developmental regulator in Drosophila. Recent studies suggest that UNK targets specific mRNAs through its two compact zinc finger clusters and regulates their translation. However, the underlying molecular mechanisms by which UNK represses translation remain unclear. To examine UNK interactions, we purified Flag-tagged UNK and subjected the preparations to Mass spectrometry (MS) and identified an enriched protein Cytoplasmic poly(A)-binding protein(PABPC1), a key component of the translation machinery that binds to the poly(A) tail of mRNAs to promote translation and mRNA turnover. GST Pull down assay and reciprocal immunoprecipitations in HEK293 cells further confirmed the strong interaction between UNK and PABPC1 and showed that the interaction is RNA-dependent. Notably, the structural analysis, along with mutational studies proved that the interaction is mediated by the C-terminal MLLE domain of PABPC1 and the C-terminal Domain of UNK both in vitro and in vivo. Further MS2 tethering assay indicated that UNK inhibits PABPC1-stimulated translation activity. Our studies identified Unkempt as a novel partner of PABPC1 that functions to represses PABPC1-stimulated translation. The findings provide novel insight into the molecular function of Unkempt and PABPC1-mediated translational machinery. Citation Format: Naren Li, Liang Hu, Qinfang Liu, Yulan Xiong, Jianzhong Yu. Translational repression by a novel partner of human cytoplasmic poly(A) binding protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 866.